抑制剂Benzamidine与胰岛素作用机制的分子动力学和结合自由能计算研究

氢键和极性相互作用在抑制剂-蛋白结合专一性识别过程中起到重要作用.抑制剂Benzamidine(BEN)与胰岛素trypsin相互作用机制的阐明有助于胰岛素高效抑制剂的研发.本文采用分子动力学模拟和MM-PBSA(molecular mechanics-Poisson Boltzmann surface area)从原子层次上研究BEN与胰岛素的结合模式.结果表明抑制剂BEN的脒基不仅与Asp189的羰基产生静电相互作用,而且与残基Ser190和Gly214形成氢键相互作用.基于残基能量分解的计算表明抑制剂的苯基与残基His58,Cys191,Gln192,Trp211,Gly212和Cys215形成有利于抑制剂结合的疏水性相互作用.期望当前的研究能为胰岛素有效抑制剂的研发提供重要的理论指导.

Insight into interaction mechanism of inhibitor Benzamidine with trypsin by using calculation of binding free energy

Hydrogen bonding and polar interactions play important part in identification of binding specificity of inhibitors to proteins. Clarification of interaction mechanism of inhibitor benzamidine (BEN) with trypsin is helpful for designs of potent inhibitors targeting trypsin. In the present work, molecular dynamics simulations and molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) were adopted to study binding mode of BEN to trypsin at atomic level. The results show that the amidinium group of BEN not only produces favorable electrostatic interactions with residue Asp189, but also form hydrogen bonding interactions with residues Ser190 and Gly214. Calculations of residue-based energy decomposition suggest that the hydrophobic phenyl of BEN generates favorable van der Waals interactions with residues His58, Cys191, Gln192, Trp211, Gly212 and Cys215. This study was expected to provide significant theoretical guidance for designs of potent inhibitors targeting trypsin.